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BACKGROUND: Myricetin, a type of flavonol commonly found in fruits and herbs, has demonstrated anticancer properties by triggering the process of apoptosis or programmed cell death in tumor cells. Despite the absence of mitochondria and nuclei, erythrocytes can undergo programmed cell death, also known as eryptosis.This process is characterized by cell shrinkage, externalization of phosphatidylserine (PS) on the cell membrane, and the formation of membrane blebs. The signaling of eryptosis involves Ca2+ influx, the formation of reactive oxygen species (ROS), and the accumulation of cell surface ceramide. The present study explored the effects of myricetin on eryptosis. METHODS AND RESULTS: Human erythrocytes were exposed to various concentrations of myricetin (2-8 µM) for 24 h. Flow cytometry was used to assess the markers of eryptosis, including PS exposure, cellular volume, cytosolic Ca2+ concentration, and ceramide accumulation. In addition, the levels of intracellular ROS were measured using the 2',7'-dichlorofluorescin diacetate (DCFDA) assay. The myricetin-treated (8 µM) erythrocytes significantly increased Annexin-positive cells, Fluo-3 fluorescence intensity, DCF fluorescence intensity, and the accumulation of ceramide. The impact of myricetin on the binding of annexin-V was significantly reduced, but not completely eliminated, by the nominal removal of extracellular Ca2+. CONCLUSION: Myricetin triggers eryptosis, which is accompanied and, at least in part, caused by Ca2+ influx, oxidative stress and increase of ceramide abundance.
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Eriptose , Humanos , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo , Eritrócitos/metabolismo , Ceramidas , Anexinas/metabolismo , Anexinas/farmacologia , Cálcio/metabolismo , Fosfatidilserinas/metabolismo , Fosfatidilserinas/farmacologia , Tamanho Celular , HemóliseRESUMO
BACKGROUND/AIMS: Vasopressin is a powerful stimulator of vascular calcification, augmenting osteogenic signaling in vascular smooth muscle cells (VSMCs) including upregulation of transcription factors such as core-binding factor α-1 (CBFA1), msh homeobox 2 (MSX2), and SRY-Box 9 (SOX9), as well as of tissue-nonspecific alkaline phosphatase (ALPL). Vasopressin-induced osteogenic signaling and calcification require the serum- and glucocorticoid-inducible kinase 1 (SGK1). Known effects of SGK1 include upregulation of Na+/H+ exchanger 1 (NHE1). NHE1 further participates in the regulation of reactive oxygen species (ROS). NHE1 has been shown to participate in the orchestration of bone mineralization. The present study, thus, explored whether vasopressin modifies NHE1 expression and ROS generation, as well as whether pharmacological inhibition of NHE1 disrupts vasopressin-induced osteogenic signaling and calcification in VSMCs. METHODS: Human aortic smooth muscle cells (HAoSMCs) were treated with vasopressin in the absence or presence of SGK1 silencing, SGK1 inhibitor GSK-650394, and NHE1 blocker cariporide. Transcript levels were determined by using quantitative real-time polymerase chain reaction, protein abundance by Western blotting, ROS generation with 2',7'-dichlorofluorescein diacetate fluorescence, and ALP activity and calcium content by using colorimetric assays. RESULTS: Vasopressin significantly enhanced the NHE1 transcript and protein levels in HAoSMCs, effects significantly blunted by SGK1 inhibition with GSK-650394 or SGK1 silencing. Vasopressin increased ROS accumulation, an effect significantly blocked by the NHE1 inhibitor cariporide. Vasopressin further significantly increased osteogenic markers CBFA1, MSX2, SOX9, and ALPL transcript levels, as well as ALP activity and calcium content in HAoSMCs, all effects significantly blunted by SGK1 silencing or in the presence of GSK-650394 or cariporide. CONCLUSION: Vasopressin stimulates NHE1 expression and ROS generation, an effect dependent on SGK1 and required for vasopressin-induced stimulation of osteogenic signaling and calcification of VSMCs.
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Calcificação Fisiológica , Calcificação Vascular , Cálcio/metabolismo , Células Cultivadas , Humanos , Miócitos de Músculo Liso , Espécies Reativas de Oxigênio/metabolismo , Trocador 1 de Sódio-Hidrogênio , Calcificação Vascular/metabolismo , Vasopressinas/metabolismoRESUMO
The key issue in the field of smart contract security is efficient and rapid vulnerability detection in smart contracts. Most of the existing detection methods can only detect the presence of vulnerabilities in the contract and can hardly identify their type. Furthermore, they have poor scalability. To resolve these issues, in this study, we developed a smart contract vulnerability detection model based on multi-task learning. By setting auxiliary tasks to learn more directional vulnerability features, the detection capability of the model was improved to realize the detection and recognition of vulnerabilities. The model is based on a hard-sharing design, which consists of two parts. First, the bottom sharing layer is mainly used to learn the semantic information of the input contract. The text representation is first transformed into a new vector by word and positional embedding, and then the neural network, based on an attention mechanism, is used to learn and extract the feature vector of the contract. Second, the task-specific layer is mainly employed to realize the functions of each task. A classical convolutional neural network was used to construct a classification model for each task that learns and extracts features from the shared layer for training to achieve their respective task objectives. The experimental results show that the model can better identify the types of vulnerabilities after adding the auxiliary vulnerability detection task. This model realizes the detection of vulnerabilities and recognizes three types of vulnerabilities. The multi-task model was observed to perform better and is less expensive than a single-task model in terms of time, computation, and storage.
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Algoritmos , Redes Neurais de Computação , Reconhecimento Psicológico , SemânticaRESUMO
In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes.
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Sinalização do Cálcio , Gadolínio/farmacologia , Cloreto de Magnésio/farmacologia , Megacariócitos/efeitos dos fármacos , Proteína ORAI1/metabolismo , Células Cultivadas , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Megacariócitos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Diabetes and chronic kidney disease (CKD) both trigger vascular osteogenic signaling and calcification leading to early death by cardiovascular events. Osteogenic signaling involves upregulation of the transcription factors CBFA1, MSX2, and SOX9, as well as alkaline phosphatase (ALP), an enzyme fostering calcification by degrading the calcification inhibitor pyrophosphate. In CKD, osteogenic signaling is triggered by hyperphosphatemia, which upregulates the serum and glucocorticoid-inducible kinase SGK1, a strong stimulator of the Ca2+-channel ORAI1. The channel is activated by STIM1 and accomplishes store-operated Ca2+-entry (SOCE). The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to high extracellular glucose concentrations similarly upregulates ORAI1 and/or STIM1 expression, SOCE, and osteogenic signaling. To this end, HAoSMCs were exposed to high extracellular glucose concentrations (15 mM, 24 h) without or with additional exposure to the phosphate donor ß-glycerophosphate. Transcript levels were estimated using qRT-PCR, protein abundance using Western blotting, ALP activity using a colorimetric assay kit, calcium deposits utilizing Alizarin red staining, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, glucose enhanced the transcript levels of SGK1 and ORAI1, ORAI2, and STIM2, protein abundance of ORAI1, SOCE, the transcript levels of CBFA1, MSX2, SOX9, and ALPL, as well as calcium deposits. Moreover, glucose significantly augmented the stimulating effect of ß-glycerophosphate on transcript levels of SGK1 and ORAI1, SOCE, the transcript levels of osteogenic markers, as well as calcium deposits. ORAI1 inhibitor MRS1845 (10 µM) significantly blunted the glucose-induced upregulation of the CBFA1 and MSX2 transcript levels. In conclusion, the hyperglycemia of diabetes stimulates expression of SGK1 and ORAI1, thus, augmenting store-operated Ca2+-entry and osteogenic signaling in HAoSMCs.
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Aorta/metabolismo , Cálcio/metabolismo , Glucose/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteína ORAI1/metabolismo , Osteogênese/fisiologia , Transdução de Sinais/fisiologia , Biomarcadores/metabolismo , Células Cultivadas , Diabetes Mellitus/metabolismo , Humanos , Hiperglicemia/metabolismo , Regulação para Cima/fisiologiaRESUMO
In chronic kidney disease, renal phosphate retention leads to hyperphosphatemia with subsequent vascular osteogenic signaling and calcification. Osteogenic signaling involves up-regulation of the transcription factors CBFA1, MSX2, and SOX9, as well as alkaline phosphatase (ALP), an enzyme stimulating calcification by degrading the calcification inhibitor pyrophosphate. Stimulation of osteogenic signaling and calcification by phosphate donor ß-glycerophosphate in human aortic smooth muscle cells (HAoSMCs) is attenuated by MgCl2, an effect mimicked by Ca2+-sensing receptor agonist GdCl3. Most recent observations revealed that the effect of ß-glycerophosphate on osteogenic signaling requires ORAI1, a Ca2+-channel accomplishing store-operated Ca2+-entry (SOCE), which is stimulated by Ca2+-sensor STIM1. The present study explored whether ORAI1 and/or STIM1 expression and, thus, SOCE and osteogenic signaling in HAoSMCs are sensitive to MgCl2 and/or GdCl3. To this end, transcript levels were estimated using q-RT-PCR, protein abundance with western blotting, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1â¯â¯µM). As a result, 24â¯h exposure to ß-glycerophosphate (2â¯mM) significantly enhanced transcript levels of ORAI1 and STIM1 as well as SOCE, effects significantly blunted or virtually abrogated by 1.5â¯mM MgCl2 and by 50â¯â¯µM GdCl3. In conclusion, MgCl2 and GdCl3 are powerful inhibitors of ORAI1 and STIM1 expression and store-operated Ca2+-entry, effects affecting osteogenic signalling in vascular smooth muscle cells.
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Cálcio/metabolismo , Cloreto de Magnésio/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Proteína ORAI1/biossíntese , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Cultivadas , Gadolínio/farmacologia , Humanos , Miócitos de Músculo Liso/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismoRESUMO
BACKGROUND: Many studies have reported the predictive value of the atherogenic index of plasma (AIP) in the progression of atherosclerosis and the prognosis of percutaneous coronary intervention (PCI). However, the utility of the AIP for prediction is unknown after PCI among type 2 diabetes mellitus (T2DM). METHODS: 2356 patients with T2DM who underwent PCI were enrolled and followed up for 4 years. The primary outcome was major cardiovascular and cerebrovascular adverse events (MACCEs), considered to be a combination of cardiogenic death, myocardial infarction, repeated revascularization, and stroke. Secondary endpoints included all-cause mortality, target vessel revascularization (TVR), and non-target vessel revascularization (non-TVR). Multivariate Cox proportional hazards regression modelling found that the AIP was correlated with prognosis and verified by multiple models. According to the optimal cut-off point of the ROC curve, the population was divided into high/low-AIP groups. A total of 821 pairs were successfully matched using propensity score matching. Then, survival analysis was performed on both groups. RESULTS: The overall incidence of MACCEs was 20.50% during a median of 47.50 months of follow-up. The multivariate Cox proportional hazards regression analysis before matching suggested that the AIP was an independent risk factor for the prognosis of T2DM after PCI (hazard ratio [HR] 1.528, 95% CI 1.100-2.123, P = 0.011). According to the survival analysis of the matched population, the prognosis of the high AIP group was significantly worse than that of the low AIP group (HR (95% CI) 1.614 (1.303-2.001), P < 0.001), and the difference was mainly caused by repeat revascularization. The low-density lipoprotein-cholesterol (LDL-C) level did not affect the prognosis of patients with T2DM (P = 0.169), and the effect of the AIP on prognosis was also not affected by LDL-C level (P < 0.001). CONCLUSIONS: The AIP, a comprehensive index of lipid management in patients with T2DM, affects prognosis after PCI. The prognosis of diabetic patients with high levels of the AIP included more MACCEs and was not affected by LDL-C levels. It is recommended to monitor the AIP for lipid management in diabetic patients after PCI and ensure that the AIP is not higher than 0.318. Trial registration This is an observational cohort study that does not involve interventions. So we didn't register. We guarantee that the research is authentic and reliable, and hope that your journal can give us a chance.
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Glicemia/metabolismo , Doença da Artéria Coronariana/terapia , Diabetes Mellitus Tipo 2/sangue , Dislipidemias/sangue , Lipídeos/sangue , Intervenção Coronária Percutânea , Idoso , Pequim/epidemiologia , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Dislipidemias/diagnóstico , Dislipidemias/mortalidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Increasing evidence has suggested that the presence of remnant lipoproteins is a significant risk factor for atherosclerosis. Remnant lipoproteins are lipoproteins that are rich in triglycerides (TGs), and the main components include very-low-density lipoprotein (VLDL) in the fasting state. Diabetic patients often have hypertriglyceridemia with elevated levels of VLDL cholesterol but normal levels of low-density lipoprotein cholesterol (LDL-C). The aim of the present study was to elucidate the potential role of remnant lipoproteins-induced atherosclerosis in the occurrence and development of in-stent restenosis (ISR) in diabetic patients with coronary artery disease. METHODS: The present study enrolled 2312 patients with type 2 diabetes mellitus who underwent percutaneous coronary intervention from January 2013 to December 2014 and who were followed up by angiography. Patients were divided into two groups based on the presence or absence of ISR, and multivariate Cox's proportional hazards regression modelling showed that remnant-like particle cholesterol (RLP-C) was an independent risk factor for ISR. According to the receiver operating characteristic curve, the optimal cutoff point of the RLP-C was identified, and the patients were further divided into 2 groups. Propensity score matching analysis was performed, and 762 pairs were successfully matched. Log-rank tests were used to compare Kaplan-Meier curves for overall follow-up to assess ISR. RESULTS: The multivariate Cox's proportional hazards regression analysis showed that RLP-C was independently associated with ISR, and the baseline RLP-C level at 0.505 mmol/L was identified as the optimal cutoff point to predict ISR. Patients were divided into 2 groups by RLP levels. After propensity score matching analysis, a total of 762 pairs matched patients were generated. Kaplan-Meier curves showed that the estimated cumulative rate of ISR was significantly higher in patients with RLP-C levels ≥ 0.505 mmol/L (log-rank P < 0.001; HR equal to 4.175, 95% CI = 3.045-5.723, P < 0.001) compared to patients with RLP-C levels < 0.505 mmol/L. CONCLUSIONS: The present study emphasized the importance of remnant-like particle cholesterol in cardiovascular pathology in diabetic patients. Physicians should take measures to control RLP-C below the level of 0.505 mmol/L to better prevent of in-stent restenosis in diabetic patients.
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Colesterol/sangue , Doença da Artéria Coronariana/cirurgia , Reestenose Coronária/sangue , Diabetes Mellitus Tipo 2/sangue , Lipoproteínas/sangue , Intervenção Coronária Percutânea/efeitos adversos , Triglicerídeos/sangue , Idoso , Pequim/epidemiologia , Biomarcadores/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/instrumentação , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Stents , Fatores de Tempo , Resultado do TratamentoRESUMO
The chemical recycling of end-of-life polylactic acid (PLA) plays roles in mitigating environmental pressure and developing circular economy. In this regard, one-pot tandem alcoholysis and hydrogenation of PLA was carried out to produce 1,2-propanediol, which is a bulk chemical in polymer chemistry. In more detail, the commercially available Raney Co was employed as the catalyst, and transformation was conducted in ethanol, which acted as nucleophilic reagent and solvent. Single-factor analysis and Box-Behnken design were used to optimize the reaction conditions. Under the optimized condition, three kinds of PLA materials were subjected to degradation. Additionally, 74.8 ± 5.5%, 76.5 ± 6.2%, and 71.4 ± 5.7% of 1,2-propanediol was yielded from PLA powder, particle, and straws, respectively, which provided a recycle protocol to convert polylactic acid waste into value-added chemicals.
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The important role of Ca2+ in pathogenic store-operated calcium entry (SOCE) is well-established. Among the proteins involved in the calcium signaling pathway, Stromal interacting molecule 1 (STIM1) is a critical endoplasmic reticulum transmembrane protein. STIM1 is activated by the depletion of calcium stores and then binds to another calcium protein, Orai1, to form a channel through which the extracellular Ca2+ can enter the cytoplasm to replenish the calcium store. Multiple studies have shown that increased STIM1 facilitates the aberrant proliferation and apoptosis of vascular smooth cells (VSMC) and macrophages which can promote the formation of rupture-prone plaque. Together with regulating the cytosolic Ca2+ concentration, STIM1 also activates STING through altered intracellular Ca2+ concentration, a critical pro-inflammatory molecule. The cGAS-STING pathway is linked with cellular proliferation and phenotypic conversion of VSMC and enhances the progression of atherosclerosis plaque. In summary, we conclude that STIM1/cGAS-STING is involved in the progression of AS and plaque vulnerability.
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Mono- and bimetallic Ni-based catalysts were prepared by screening 6 supports and 14 secondary metals for reductive amination of 5-hydroxymethylfurfural (5-HMF) into 2,5-bis(aminomethyl)furan (BAMF), among which γ-Al2 O3 and Mn were the best candidates. By further optimization of the reaction conditions at 0.4â g catalyst loading for 0.5â g substrate of 5-HMF and 160 °C of reaction temperature, 10Ni/γ-Al2 O3 and 10NiMn(4 : 1)/γ-Al2 O3 achieved the highest BAMF yields of 86.3 and 82.1 %, respectively. Although the BAMF yield values were comparable with that over Raney Ni, the turnover frequencies based on the initial BAMF yield and unit weight of Ni for 10NiMn(4 : 1)/γ-Al2 O3 , 10Ni/γ-Al2 O3 , and Raney Ni were calculated as 0.41, 0.09, and 0.04â h-1 , respectively. X-ray diffraction, transmission electron microscopy, and X-ray photoelectron spectroscopy showed that the existence of MnOx well dispersed on the γ-Al2 O3 support and its electron transfer effect with Ni particles on the surface of the support contributed to the high efficiency and better recyclability for the five-time reused 10NiMn(4 : 1)/γ-Al2 O3 catalyst.
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Óxido de Alumínio , Furaldeído , Óxido de Alumínio/química , Aminação , Furaldeído/análogos & derivados , Furaldeído/química , Furanos/químicaRESUMO
In this study, we designed and synthesized twelve bitopic ligands as dopamine D2 receptor (D2 R) agonists. The forskolin-induced cAMP accumulation assay revealed that all the finial compounds are able to activate D2 R. Furthermore, bitopic ligand N-((trans)-4-(((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclo-hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (11 b) showed 21-fold higher potency than lead compound propyl aminoindane (2) and 17-fold higher subtype selectivity for D2 R over D4 R, indicating that the optimal length of spacer affects the D2 R functionality. Molecular modeling study exhibited that 11 b formed an electrostatic interaction and two H-bonds with amino acid Asp114, which contributes significantly to the D2 R functional activity. Taken together, we discovered a bitopic ligand 11 b as potent D2 R agonist, which may be used as a tool compound for further study.
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Indanos/farmacologia , Piridinas/farmacologia , Receptores de Dopamina D2/agonistas , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indanos/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
We evaluated the predictive power of the atherogenic index of plasma (AIP) for coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). A total of 3278 patients who underwent coronary angiography were consecutively enrolled, including 2052 patients with CAD and 1226 patients with T2DM but without CAD. Patients in the CAD group had higher levels of triglyceride (TG), total cholesterol, low-density lipoprotein cholesterol, AIP and a lower level of high-density lipoprotein cholesterol (HDL-C). In correlation analyses, AIP correlated positively with body mass index, log (homeostasis model assessment of insulin resistance), TG, remnant lipoprotein cholesterol, non-HDL-C, but negatively with age and HDL-C. Multivariate logistic regression analyses demonstrated that AIP was an independent risk factor for CAD in diabetic patients and was validated by multiple models. Furthermore, the ORs for CAD risk were raised with increasing AIP quartiles; ORs of AIP quartiles Q2-Q4 compared with Q1 were 1.56, 1.70, and 2.22, respectively (Ps < .001), which suggested AIP was the lipid parameter that most strongly associated with incident CAD. In conclusion, AIP is a powerful and reliable biomarker for predicting CAD risk beyond individual lipid profiles in patients with T2DM.
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Colesterol/sangue , Doença da Artéria Coronariana/sangue , Diabetes Mellitus Tipo 2/sangue , Dislipidemias/sangue , Triglicerídeos/sangue , Idoso , Pequim/epidemiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Dislipidemias/complicações , Dislipidemias/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de RiscoRESUMO
Vascular calcification may result from stimulation of osteogenic signalling with upregulation of the transcription factors CBFA1, MSX2 and SOX9, as well as alkaline phosphatase (ALPL), which degrades and thus inactivates the calcification inhibitor pyrophosphate. Osteogenic signalling further involves upregulation of the Ca2+-channel ORAI1. The channel is activated by STIM1 and then accomplishes store-operated Ca2+ entry. ORAI1 and STIM1 are upregulated by the serum & glucocorticoid inducible kinase 1 (SGK1) which is critically important for osteogenic signalling. Stimulators of vascular calcification include vasopressin. The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to vasopressin upregulates ORAI1 and/or STIM1 expression, store-operated Ca2+ entry and osteogenic signalling. To this end, HAoSMCs were exposed to vasopressin (100 nM, 24 h) without or with additional exposure to ORAI1 blocker MRS1845 (10 µM) or SGK1 inhibitor GSK-650394 (1 µM). Transcript levels were measured using q-RT-PCR, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and store-operated Ca2+ entry from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, vasopressin enhanced the transcript levels of ORAI1 and STIM1, store-operated Ca2+ entry, as well as the transcript levels of CBFA1, MSX2, SOX9 and ALPL. The effect of vasopressin on store-operated Ca2+ entry as well as on transcript levels of CBFA1, MSX2, SOX9 and ALPL was virtually abrogated by MRS1845 and GSK-650394. In conclusion, vasopressin stimulates expression of ORAI1/STIM1, thus augmenting store-operated Ca2+ entry and osteogenic signalling. In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394. KEY MESSAGES: ⢠In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. ⢠VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). ⢠VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. ⢠VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394.
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Sinalização do Cálcio/efeitos dos fármacos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Proteína ORAI1/biossíntese , Calcificação Vascular/metabolismo , Vasopressinas/farmacologia , Aorta/citologia , Benzoatos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/fisiologia , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Imediatamente Precoces/fisiologia , Miócitos de Músculo Liso/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Nitrendipino/análogos & derivados , Nitrendipino/farmacologia , Proteína ORAI1/antagonistas & inibidores , Proteína ORAI1/genética , Osteogênese/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/fisiologia , Molécula 1 de Interação Estromal/biossíntese , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/fisiologia , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Calcificação Vascular/prevenção & controleRESUMO
BACKGROUND: Tanscatheter left atrial appendage (LAA) closure and minimally invasive thoracoscopic LAA occlusion are local interventions of LAA for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, the safety and efficacy of these methods have not been compared. This prospective cohort study aimed to assess the safety and efficacy of those two treatment approaches for stroke prevention in NVAF patients. METHODS: Two hundred and nine recurrent NVAF patients who received radiofrequency ablation were enrolled. These patients were treated with transcatheter LAA closure or thoracoscopic LAA occlusion. The patients were followed up from the first postoperative day and evaluated for efficacy endpoints (stroke/transient ischemic attack (TIA), systemic embolism (SE), and death) and a safety endpoint (bleeding events). Perioperative complications were recorded. RESULTS: After a median follow-up of 1.8 years (383 patient-years), the overall rate of the composite efficacy endpoints was similar between the two groups (3.8 vs. 2.7 events per 100 patient-years; HR = 0.71; 95% CI: 0.225-2.237; P = 0.559). However, regarding primary safety endpoint, there were 1.5 bleeding events per 100 patient-years in the thoracoscopic LAA occlusion group, compared with 6.4 in transcatheter LAA closure group (HR = 0.246; 95% CI: 0.074-0.819; P = 0.022). The incidence of operative complications was 3/138 (2.17%) in thoracoscopic LAA occlusion group and 1/71 (1.41%) in transcatheter LAA closure group. CONCLUSIONS: Thoracoscopic LAA occlusion and transcatheter LAA closure have similar efficacy in preventing stroke in NVAF patients. However, the thoracoscopic group had fewer bleeding events than the transcatheter group, but the former group required a longer hospital stay.
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Simultaneous reductive amination of C=O and C-OH in 5-hydroxymethylfurfural (HMF) into C-NH2 in 2,5-bis(aminomethyl)furan (BAMF) is challenging. In this work, reductive amination of C=O in HMF was firstly studied, in which HMF can be converted into 5-hydroxymethyl furfurylamine (HMFA) with a 99.5 % yield over Raney Co catalyst. BAMF was then directly synthesized with 82.3 % yield from HMF over Raney Ni catalyst at 160 °C for 12â h. An even higher yield of 88.3 % could be obtained through a stepwise reductive amination process, in which the reaction started at 120 °C for the first 2â h over Raney Co mainly for amination of C=O and then continued at 160 °C for another 10â h over Raney Ni mainly for amination of C-OH. Under optimized reaction conditions, the catalyst could be reused four times without obvious loss in catalytic performance. XRD and XPS characterization of the reused catalyst indicated that the formation of Ni3 N and the adsorption of alkyl amines could be the main reasons for the deactivation of the catalyst. Moreover, plausible reaction pathways were proposed to originate the detected by-products according to the kinetic profiles.
RESUMO
Studies on chronic total occlusion (CTO) treatment strategy in stable patients have reported conflicting results. We focused on stable diabetic patients with a single CTO (other vessels have been successfully treated before). We attempted to identify which strategy (percutaneous coronary intervention [PCI] or medical therapy [MT]) is optimal; 545 patients were selected from a total of 39 952 patients. Based on the initial treatment strategy, we assigned patients to either the PCI or MT group. The primary end point was a major adverse cardiac event (MACE). After a median follow-up of 45 months (interquartile range: 25.7-79.2 months), we observed (1) no difference in MACE and myocardial infarction between groups, (2) multivariate analysis showed that PCI group was superior to MT group in cardiac death (hazard ratio: 4.758 (1.698-13.334); P = .003) and all-cause death (2.767 [1.157-6.618]; P = .022). The superiority was consistent in propensity score-matched analysis, and (3) a failed PCI group was not associated with higher risks in the clinical end points, except for target vessel revascularization, compared with MT. We concluded that for stable patients with diabetes and one single CTO, initial PCI strategy tended to offer patients survival benefits compared with MT.
Assuntos
Oclusão Coronária/tratamento farmacológico , Oclusão Coronária/cirurgia , Angiopatias Diabéticas/cirurgia , Intervenção Coronária Percutânea , Idoso , Doença Crônica , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos RetrospectivosRESUMO
Thoracoscopic left atrial appendage (LAA) occlusion is an alternative treatment for stroke prevention in patients with atrial fibrillation. Prospective study comparing thoracoscopic LAA occlusion and warfarin therapy is still lacking. The goal of this prospective cohort study was to assess the safety and efficacy of thoracoscopic LAA occlusion for stroke prevention in patients with nonvalvular atrial fibrillation compared with long-term warfarin therapy. Four hundred and ninety-two nonvalvular atrial fibrillation patients were enrolled. Two hundred and fifty-seven patients were treated with thoracoscopic LAA occlusion and 235 with long-term warfarin therapy. At 24 months, the rate of the first efficacy endpoint (composite of stroke, systemic embolism, and death) was 0.018 in the surgical group versus 0.043 in the warfarin group (pâ¯=â¯0.033). The rate of the second efficacy endpoint (stroke and systemic embolism excluding the first 7 days after procedure) was 0.010 versus 0.034 (pâ¯=â¯0.019). The rate of the first safety endpoint of bleeding was 0.016 versus 0.044 (pâ¯=â¯0.022). In conclusion, this study showed that thoracoscopic LAA occlusion was superior to warfarin for stroke prevention. The surgical group also had significantly lower bleeding risk. The incidence of surgical complications was low, and all occurred in hospital without causing serious outcomes.
Assuntos
Anticoagulantes/administração & dosagem , Apêndice Atrial/cirurgia , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/cirurgia , Acidente Vascular Cerebral/prevenção & controle , Toracoscopia , Varfarina/administração & dosagem , Idoso , Ecocardiografia Transesofagiana , Feminino , Humanos , Masculino , Estudos Prospectivos , Ablação por Radiofrequência , Resultado do TratamentoRESUMO
BACKGROUND: For patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) undergoing primary percutaneous coronary intervention (PCI), the optimal timing of the initiation of intra-aortic balloon pump (IABP) therapy remains unclear. Therefore, we performed the first meta-analysis to compare the outcomes of IABP insertion before vs after primary PCI in this population. METHODS: Electronic databases of PubMed, EMBASE, and Cochrane Library were comprehensively searched from inception to April 1, 2019, to identify the eligible studies. The main outcomes were short-term (in-hospital or 30 days) and long-term (≥ 6 months) mortality. In addition, pooled analysis of risk-adjusted data were also performed to control for confounding factors. RESULTS: Seven observational studies and two sub-analysis of randomized controlled trials involving 1348 patients were included. Compared to patients inserted IABP after PCI, patients who received IABP therapy before primary PCI had similar risks of short-term (odds ratio [OR] 0.88, 95% CI 0.49 to 1.59) and long-term (OR 0.99, 95% CI 0.58 to 1.68) all-cause mortality. Moreover, a pooled analysis of risk-adjusted data also found similar effects of the two therapies on short-term (OR 0.65, 95% CI 0.34 to 1.25) and long-term (OR 0.68, 95% CI 0.17 to 2.72) mortality. Besides, no significant difference was found between the two groups with respect to reinfarction, repeat revascularization, stroke, renal failure, and major bleeding. CONCLUSIONS: The timing of the initiation of IABP therapy does not appear to impact short-term and long-term survival in patients with AMI complicated by CS undergoing primary PCI.